Epothilone A (1, FIG. 1) and epothilone B (2, FIG. 1) are natural substances isolated from myxobacteria Sorangium cellulosum strain 90. These natural substances exhibit cytotoxicity against taxol-resistant tumor cells and may prove to have a clinical utility comparable or superior to Taxol. (For Taxol references see: Horwitz et al. Nature 277, 665–667 (1979); Nicolaou et al. Angew. Chem. Int. Ed. Engl. 33, 15–44 (1994).) Uke taxol, the epothilones are thought to exert their cytotoxicity by induction of microtubule assembly and stabilization. (Bollag et al. Cancer Res. 55, 2325–2333 (1995); Kowalski et al. J. Biol. Chem. 272, 2534–2541 (1997).) Epothilones are reported to be about 2000–5000 times more potent than Taxol with respect to the stabilization of microtubules. Despite the marked structural differences between the epothilones and Taxol™, the epothilones were found to bind to the same region on microtubules and to displace Taxol™ from its binding site. (Grever et al. Seminars in Oncology 1992, 19, 622–638; Bollag et al. Cancer Res. 1995, 55, 2325–2333; Kowalski et al. J. Biol. Chem. 1997, 272, 2534–2541; Horwitz et al. Nature 1979, 277, 665–667; Nicolaou et al. Angew. Chem. Int. Ed. Engl. 1994, 33, 15–44.) Epothilones A and B have generated intense interest amongst chemists, biologists and clinicians due to their novel molecular architecture, important biological action and intriguing mechanism of action. (Höfle et al. Angew. Chem. Int. Ed. Engl. 35, 1567–1569 (1996); Grever et al. Semin. Oncol. 19, 622–638 (1992); Bollag et al. Cancer Res. 55, 2325–2333 (1995); Kowalski et al. J. Biol. Chem. 272, 2534–2541 (1997); Nicolaou et al. Angew. Chem. Int. Ed. Engl. 35, 2399–2401 (1996); Meng et al. J. Org. Chem. 61, 7998–7999 (1996); Bertinato et al. J. Org. Chem. 61, 8000–8001 (1996); Schinzer et al. Chem. Eur. J. 2, 1477–1482 (1996); Mulzer et al. Tetrahedron Lett. 37, 9179–9182 (1996); Claus et al. Tetrahedron Lett. 38, 1359–1362 (1997); Gabriel et al. Tetrahedron Lett. 38, 1363–1366 (1997); Balog et al. Angew. Chem. Int. Ed. Engl. 35, 2801–2803 (1996); Yang et al. Angew. Chem. Int. Ed. Engl. 36, 166–168 (1997); Nicolaou et al. Angew. Chem. Int. Ed. Engl. 36, 525–527 (1997); Schinzer et al. Angew. Chem. Int. Ed. Engl. 36, 523–524 (1997); Meng et al. J. Am. Chem. Soc. 119, 2733–2734 (1997).)
What is needed are analogs of epothilone A and B and libraries of analogs of epothilone A and B that exhibit superior pharmacological properties in the area of microtubule stabilizing agents.
What is needed are methods for producing synthetic epothilone A, epothilone B, analogs of epothilone A and B, and libraries of epothilone analogs, including epothilone analogs possessing both optimum levels of microtubule stabilizing effects and cytotoxicity.